Liquid chromatography in open tubular columns offers the potential for chemical separations with extraordinarily high resolving power while requiring analysis times of only a few hours. Improvements in resolving power of ten to thirty fold over conventional packed column technology should be possible. Such separations will require development of columns with internal diameters of only one to five microns. An additional asset of such columns is their suitability for use in the analysis of samples of extremely small volume (nanoliters to picoliters), such as the contents of individual cells. The proposed work will concentrate on four main areas. 1. The development of technology for the fabrication of open tubular columns of diameters less than ten microns. Also, the development of the technology to permit effective gradient elution with these columns. 2. The development of detectors based on a variety of principles which are sensitive enough to work effectively with columns of such small diameter. 3. The exploration of the use of these columns in the analysis of the contents of single cells, such as neurons. 4. The application of these chromatographic systems for the analysis of complex mixtures of biomedical origin. This will include metabolic profiling studies as well as the investigation of new techniques, based on the high resolving power of open tubular columns, for the use of stable isotopes in metabolic tracer experiments. Liquid chromatographic columns, capable of separating several hundred components in a single run, will make possible more effective analyses of the exceedingly complex mixtures characteristic of biological tissues and fluids. The ability to analyze the complex mixture of organic constituents of single cells will offer exciting new approaches to studies in the life sciences and revolutionize such fields as the neurosciences.